| Prophylactic/therapeutic agent for alzheimer's disease -> Monitor Keywords |
|
|
 
Prophylactic/therapeutic agent for alzheimer's diseaseProphylactic/therapeutic agent for alzheimer's disease description/claimsThe Patent Description & Claims data below is from USPTO Patent Application 20090270439, Prophylactic/therapeutic agent for alzheimer's disease. Brief Patent Description - Full Patent Description - Patent Application Claims
The present invention relates to a medicament for prophylaxis and treatment of Alzheimer disease comprising as an active ingredient apomorphine hydrochloride. More specifically, the present invention relates to a medicament for prophylaxis and treatment of Alzheimer disease comprising as an active ingredient apomorphine hydrochloride wherein the medicament acts through inhibition of intracellular accumulation of amyloid β and/or p53 dependent cell death. Alzheimer disease is in particular a serious issue in Japan where dwindling birthrate is remarkable and aging society has progressed, as its number of patients keeps on increasing (there are 1.6 to 1.8 million patients as of 2005 in Japan). Although research of Alzheimer disease has extensively been done for addressing this issue, an eradicative medicine has not been developed that allows for determent of neuronal death, the key to the development of the disease. A hypothesis of amyloid cascade has been proposed as a mechanism of onset of Alzheimer disease. According to this hypothesis, an amyloid β protein precursor (hereinafter also referred to as “APP”) is cleaved by β- and γ-secretases to produce an amyloid β protein (hereinafter also referred to as “Aβ”) which aggregates and accumulates to thereby cause destruction of cerebral neurons and fall-off of the cerebral nerve. An amyloid β protein precursor, a parent glycoprotein of an amyloid β protein that is a major cause of Alzheimer disease, remains to be elucidated for its function. On the other hand, an amyloid β protein is a major component of “senile plaque” typically found in Alzheimer disease patients with a molecular weight of about 4 kDa, among which three types of Aβ40, Aβ42 and Aβ43 are known based on the number of amino acid residues. It is known that an amyloid β protein as a major cause of Alzheimer disease may have a low cytotoxicity in its monomer form but exert a potent toxicity in its oligomer form upon aggregation. Aggregation of an amyloid β protein causes destruction of cerebral neurons and fall-off of the cerebral nerve to thereby form amyloid plaques and neurofibrillary changes, which trigger the cause of cell death of cerebral neurons and fall-off of neurons such as acetylcholinergic neurons, ultimately resulting in onset of Alzheimer disease. A medicament approved to be efficacious to symptoms characteristic to Alzheimer disease such as recognition disturbance and defects of memory includes chiefly one increasing an acetylcholine level in the brain, i.e. a choline esterase inhibitor, based on the notion that intracerebral disturbance of acetylcholinergic nerve in patients suffering from Alzheimer disease is the cause of the disease. There is only one such a medicament in Japan, “ARICEPT” (Donepezil HCI; Eisai Co., Ltd.), which is a choline esterase inhibitor. The sales of ARICEPT in Japan at the first quarter of 2005 are 35.1 billion yen, 23% higher than the previous year, and 162.9 billion yen worldwide, 15% higher than the previous year. However, ARICEPT merely restrictedly suppresses the aggravation of symptoms of Alzheimer disease but is never an eradicative medicine of the disease. It is estimated that only 47% of Alzheimer disease patients in Japan actually undergo therapeutic treatment and thus a market of a medicament for treating dementia is expected to keep growing from now on to accelerate the research and development of the drugs. With the knowledge that neurodegeneration progresses by neurotoxicity of an extracellular amyloid β protein, especially Aβ42, therapeutic strategy many researchers and enterprises currently envisage includes, for preventing the neurodegeneration, an inhibitor of β- and γ-secretases that produce an amyloid β protein, an activator of neprilysin (RIKEN) that degrades an extracellular amyloid β protein, an inhibitor of polymerization of an amyloid β protein, and in particular vaccination. For vaccination, an amyloid β protein is administered to patients as a vaccine so as to produce an antibody thereto wherein said antibody would remove senile plaques and inhibit aggregation and deposition of secreted amyloid β proteins to thereby prevent fall-off of neurons. In either therapeutic medicament, however, severe adverse side effects such as encephalitis are observed and neurodegeneration per se is not actually inhibited and thus eradication of Alzheimer disease would not be possible. Recently, toxicity of amyloid β proteins (Aβ42) accumulated within neurons has been focused and, as a mechanism, its action at endoplasmic reticulum, mitochondria and synapse has been proposed in several treatises (Non-patent references 1, 2, 3 and 4). However, the action at nucleus or a mechanism directly leading to apoptosis has not yet been reported. The accumulation of amyloid β proteins (Aβ42) within neurons is induced by excessive oxidative stress such as hydrogen peroxide associated with aging of the brain and, although neurons do not die at this stage, risk leading to apoptosis is quite increased. When amyloid β proteins (Aβ42) accumulated within neurons are transferred to nucleus, cell death is accelerated through increased expression of p53. Recently, Aβ-related Death Inducing Protein (AB-DIP) has been identified as a molecular chaperone that transfers Aβ from cytoplasm to nucleus (Non-patent reference 5). Functional acceleration of this molecule would induce apoptosis of cells which is known to be Aβ dependent. Therefore, not only damages in mitochondria, endoplasmic reticulum and synapse but also a pathway of Aβ transfer to nucleus as directly leading to p53 dependent apoptosis is thought to be most important. Viewing that acceleration of intracellular Aβ42/p53 dependent apoptosis may deeply be involved in fall-off of neurons observed in as high as 90% or more of the brain affected with Alzheimer disease, blockage of this pathway would extremely be important. As a strategy, it is considered to be rational to accelerate degradation of Aβ accumulated in cytoplasm and of p53 by activation of proteasome function. The reason for this includes that: 1) Aβ accumulated in cytoplasm may possibly damage mitochondria and synapse even not through apoptosis; 2) functional decline of proteasome in neurons due to aging or Alzheimer disease is reported (Non-patent reference 6); 3) it will be convenient to target proteasome since proteasome degrades both Aβ42 and p53; and 4) accumulation of abnormal proteins in neurons has been observed not only in Alzheimer disease but also in e.g. Parkinson disease or spinocerebellar degeneration and thus suppression of neurodegenerative mechanism in general may be expected. Proteasome is a gigantic multi-component complex consisted of about 50 subunits in total having a molecular weight of about 2 million and is said to be the biggest and the most complex enzyme in the history of biochemistry. It localizes in nucleus and cytoplasm and selectively degrades intracellular proteins. Its main targets are many proteins involved in cell cycle, growth and apoptosis. Most of proteins of short life are degraded through ubiquitin/proteasome pathway. This ubiquitin/proteasome pathway is deeply involved in various life phenomena such as metabolism, cell cycle, apoptosis, positive/negative signaling, quality control of proteins, stress and immunological response and draws attention as being a new control system of living reactions different from the control by biosynthesis of proteins as recognized so far. It is well foreseeable that breakdown of this control system will lead to the cause of various pathological conditions and therefore research of a medicament that may positively and/or negatively control this control system would contribute to development of therapy efficacious for a variety of intractable diseases currently difficult to deal with. Since 1869 when apomorphine hydrochloride was initially used as an emetic, it has been used as a sedative for patients suffering from schizophrenia and also as a behavior-improving agent for patients suffering from alcoholic or narcotic intoxication during the first half of the 21st century. In Japan, it has been described in Japan Pharmacopoeia from the 1st edition (issued in 1886) up to the 7th revision (issued in 1966; Part 2) and also in National Formulary. It has been clinically used as an emetic with a high dosage (normal dose: 5 mg, subcutaneous; maximum dose: 20 mg, subcutaneous) or as an expectorant with a low dosage (0.5-1 mg/dose). In 1967, apomorphine hydrochloride was found to be efficacious as a dopamine agonist and begun to be clinically used as an anti-Parkinson disease agent. In Europe, it is currently used as an anti-Parkinson disease agent (subcutaneous; 1.5-10 mg/dose, 2-8 doses/day). Relevancy between apomorphine hydrochloride and Alzheimer disease is not known up till the present. It is reported that a certain apomorphine analogue accelerates oligomerization of amyloid β proteins and inhibits fibrillization thereof (Non-patent reference 7). However, this report merely concerns the action and mechanism in the extracellular amyloid cascade hypothesis. There is also a report that a glycoside and a orthoester glycoside derivative of apomorphine and analogue is used for treatment and amelioration of disorders including Alzheimer disease and amnesia and/or dementia (Non-patent references 1 and 2). However, this report focuses on the treatment of functional disorder of erection but fails to teach any of the action and mechanism against Alzheimer disease or pharmacological effects. Patent reference 1: Japanese Patent Publication No. 2005-526790
|
 * Protect your Inventions * US Patent Office filing 
PATENT INFO |
|
How KEYWORD MONITOR works... a FREE service from FreshPatents